{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:03:27Z","timestamp":1790672607636,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Development of therapies and pharmacological management of central nervous system diseases is significantly hampered by the presence of the highly selective blood\u2013brain barrier (BBB). Receptor-mediated transcytosis (RMT) has proven to be a robust mechanism for delivering a wide variety of therapeutic modalities across the BBB. The present study describes the use of a neurotensin-based pharmacodynamic model to evaluate the brain penetrating capacity of FC5, a well-characterized RMT shuttle. Here we produce fusion molecules of FC5 with human Fc and neurotensin and show that intact but not C-terminally clipped neurotensin proteins containing either FC5 (FC5Fc-neurotensin) or a non-BBB-crossing control (A20.1Fc-neurotensin) retain the ability to activate neurotensin receptor type 1. In in vivo studies, intravenous administration of FC5Fc-neurotensin, but not neurotensin alone or A20.1Fc-neurotensin, induced a drop in the core body temperature in both rats and mice. We further extended these findings to non-human primates, demonstrating the ability of FC5 to cross the BBB in this species. Collectively, our results further support the potential of FC5 in delivering payloads across the BBB. The neurotensin model of hypothermia is also validated as a pharmacodynamic approach for assessing brain delivery, albeit with some necessary considerations into the molecular characterization of fusion constructs before in vivo evaluation.<\/jats:p>","DOI":"10.3390\/cells15191770","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:12:42Z","timestamp":1790669562000},"page":"1770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Changes in Core Temperature Following Administration of FC5, a Blood\u2013Brain Carrier Fused with Neurotensin in Mice, Rats and Non-Human Primates"],"prefix":"10.3390","volume":"15","author":[{"given":"Alvaro","family":"Yogi","sequence":"first","affiliation":[{"name":"Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Etienne","family":"Lessard","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Eric","family":"Brunette","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6958-1725","authenticated-orcid":false,"given":"Christie E.","family":"Delaney","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2454-8989","authenticated-orcid":false,"given":"Arsalan S.","family":"Haqqani","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6464-736X","authenticated-orcid":false,"given":"Anna","family":"Robotham","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Wael","family":"Alata","sequence":"additional","affiliation":[{"name":"Biology Program, Division of Science, New York University Abu Dhabi, Saadiyat Island Campus, Abu Dhabi P.O. Box 129188, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Maria J.","family":"Moreno","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Danica B.","family":"Stanimirovic","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12987-020-00230-3","article-title":"A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity","volume":"18","author":"Kadry","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuropharm.2016.03.021","article-title":"The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes","volume":"120","author":"Gribkoff","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1080\/17425247.2023.2286371","article-title":"Strategies to identify, engineer, and validate antibodies targeting blood-brain barrier receptor-mediated transcytosis systems for CNS drug delivery","volume":"20","author":"Choi","year":"2023","journal-title":"Expert Opin. 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